1. Field Of The Invention
This invention relates to a process for preparing 3-alkoxymethylcephalosporins which are useful as intermediates for various cephalosporin derivatives having a high antimicrobial activity across a broad antimicrobial spectrum. More particularly, the present invention relates to a process for preparing a 3-alkoxymethyl-3-cephem-4-carboxylic acid represented by the formula (II) or its derivative, or a salt thereof, ##STR1## wherein R.sub.1 represents an amino group or a protected amino group, R.sub.2 represents a hydrogen atom or a lower alkoxy group and R.sub.3 represents an unsubstituted or substituted lower alkyl group,
which can be easily carried out on a commercial scale and which can give the desired product in high yield.
2. Discussion Of Related Art
As a process for preparing a 3-alkoxymethyl-3-cephem-4-carboxylic acid represented by the formula (II), there have heretofore been proposed, for example, a method (1) in which the corresponding 3-acetoxymethyl compound is reacted with a lower aliphatic alcohol in the absence of a catalyst (see, for example, U.S. Pat. Nos. 3,665,003, 3,790,567 and 3,846,416), a method (2) in which the corresponding 3-hydroxymethyl compound is reacted with an alkylating agent (see, for example, U.S. Pat. Nos. 3,665,003, 3,790,567 and 3,846,416), a method (3) in which the corresponding 3-halomethyl compound is reacted with a lower aliphatic alcohol (see, for example, U.S. Pat. Nos. 3,658,799 and 3,948,906), a method (4) in which the corresponding 3-haloacetoxymethyl compound is reacted with a lower aliphatic alcohol (see, for example, U.S. Pat. Nos. 3,658,799 and 3,948,906), and a method (5) in which the corresponding .DELTA..sup.2 -3-halomethyl compound is reacted with a lower aliphatic alcohol and then subjected to isomerization [see, for example, J. Med. Chem. 14, 113(1971)].
None of the above-mentioned conventional methods (1), (2), (3), (4) and (5) can be satis factorily practiced on a commercial scale. According to method (1), the yield of the desired product is as low as about 10 %. In method (2), it is disadvantageously necessary not only to protect the carboxyl group at the 4-position, but also to use toxic diazomethane in a large amount. According to method (3), it is also disadvantageously necessary to prepare the 3-halomethyl compound from the corresponding 3-acetoxymethyl compound through two steps and then to protect the carboxyl group at the 4-position and, in addition, the yield of the desired product is low. According to method (4), it is disadvantageously necessary to prepare the 3-haloacetoxymethyl compound from the corresponding 3-acetoxymethyl compound through three to four steps and, in addition, the yield of the desired product is low. Further, according to method (5), there are involved such a sequence of many steps that the starting .DELTA..sup.3 -3-methyl compound is isomerized to the corresponding .DELTA..sup.2 -3-methyl compound, followed by halogenation to obtain the corresponding .DELTA..sup.2 -3 -halomethyl compound and, after the reaction of the .DELTA..sup.2 -3-halomethyl compound with a lower aliphatic alcohol, the reaction product is again isomerized to the corresponding 3-cephem compound.
Further, there has also been proposed a method (6) in which the corresponding 3-acetoxymethyl compound is reacted with a lower aliphatic alcohol in the presence of a bromide, iodide or chloride, for example, a metal iodide such as lithium iodide, sodium iodide, magnesium iodide or the like; a quarternary ammonium iodide such as N-methylpyridinium iodide or the like; and a chloride or bromide of an alkali metal, an alkaline earth metal or a quaternary ammonium (see, for example, U.S. Pat. No. 4,482,710 and Japanese Pat. Application Laid-Open Specification No. 57-192392). A method (7) has also been proposed in which the corresponding 3-acetoxymethyl compound (7-aminocephalosporanic acid) is reacted with a lower aliphatic alcohol in the presence of a sulfonic acid or its derivative (Japanese Pat. Application Laid-Open Specification No. 59-163387). A method (8) has been proposed in which the corresponding 3-acetoxymethyl compound (7-aminocephalosporanic acid) is reacted with a lower aliphatic alcohol in the presence of boron trifluoride or a complex of boron trifluoride (European Pat. Application Publication No. 204657). Likewise, methods ( 6), (7) and (8) are commercially disadvantageous in that the yield of the desired product is low and complicated steps are required for isolating the desired product.
Therefore, there is still a strong demand in the art for an improved process of preparing a 3-alkoxymethyl-3-cephem-4-carboxylic acid.